Quinoxaline is one of the truly important nitrogen-containing heterocycles and versatile
building blocks for the synthesis of natural products, pharmaceutical agents,[1] and other biologically active compounds.[2] The scaffold is linked with a number of pharmacological activities such as anticancer-,[3] antifungal-,[4] antiviral-,[5] antimalarial-,[6] antibacterial-,[7] and immunosuppressive/antineoplastic activities[8] (Figure [1]). Moreover, the quinoxaline scaffold is also employed in a range of applications
as dyes,[9] organic semiconductors,[10] anion receptors,[11] dehydroannulenes,[12] cavitands,[13] electroluminescent materials,[14] and DNA-cleaving agents.[15] Quinoxalines are central components of several important antibiotics such as echinomycin,
levomycin, and actinoleutin.[16]
Figure 1 Some biologically important quinoxalines
The range of applications of quinoxalines has triggered the development of numerous
synthetic methods for their synthesis.[17] The direct condensation between 1,2-aryldiamines and 1,2-dicarbonyl compounds has
been known since the late 1800s and is, arguably, one of the most widely known reactions
in organic chemistry.[17c]
[d] A simple Scifinder search on the archetypical reaction between phenylenediamine
and glyoxal reveals an astounding 48121 hits, truly underlining the power and widespread
knowledge of this classical transformation. Some of the contemporary approaches towards
quinoxalines also include the classical cyclocondensation and can be summarized as
follows (Scheme [1]): (a) the condensation reaction between diamines and dicarbonyl compounds under
reflux in ethanol or acetonitrile with catalyst or acid present,[18] (b) reaction between vicinal diols and diamines in the presence of variety of metal
catalysts and strong bases,[19] (c) reaction with α-hydroxy ketones using MnO2 and CuCl2 as catalysts,[20] and (d) the condensation of diamines with α-halo ketones – used for the synthesis
of quinoxalines in the presence of TMSCl and HClO4–SiO2 as heterogeneous catalysts at elevated temperatures.[21]
Scheme 1 Synthetic strategies for quinoxaline formation via phenylenediamines
There are several improvements in synthetic procedures reported using microwave irradiation,[22] solid-phase synthesis,[23] ultrasound,[24] as well as solvent-free[25] and room-temperature conditions.[25] Numerous catalyst systems have been reported for the synthesis of quinoxalines,
including iodine,[26] acetic acid,[27] zeolites,[28] Ni nanoparticles,[29] ionic liquids,[30] NH4Cl,[31] Al2O3,[32] MnO2,[33] POCl3,[34] Pd(OAc)2,[35] cerium ammonium nitrate,[36] gallium triflate,[37] CuSO4·5H2O,[38] and sulfamic acid/methanol.[39] In general, the reported methods often require elevated temperatures, strong acid
catalyst, stoichiometric oxidant, expensive metal catalysts, or relatively long reaction
times to facilitate the reaction with reasonable synthetic efficiency. Moreover, many
of these methods typically display low-atom economy and yield undesirable byproducts.
Thus, the development of highly efficient, simple, and environmentally benign reaction
conditions is an important goal. In this regard, it can be noted that roughly half
of the Scifinder hits on the reaction between phenylenediamine and glyoxal were classified
as uncatalyzed, i.e., occurred with only heating and/or prolonged reaction times.
In this myriad of reported conditions, it is difficult to navigate when considering
the synthesis of a specific quinoxaline. In this paper, we intend to convey with clarity
where to start.
It is often difficult to find a rationale for the use of all the different catalysts
and additives that have been reported. However, it is well known that the condensation
reaction can be catalyzed by Lewis or Brønsted acids.[18]
[19] Moreover, the shear diversity and quantity of reaction conditions reported suggest
that the condensation is very robust and tolerant. With this perspective, we have
aimed to overcome typical limitations and to identify the most practical and simple
reaction conditions for this classical transformation from which any optimization
work should start. Herein, we demonstrate a very simple, high-yielding/highly atom-economic
protocol for the synthesis of quinoxalines using diamines and dicarbonyl compounds
in methanol as solvent at room temperature with only one-minute reaction time. To
our surprise, previous accounts have not described the broad use and scope of the
very simplest conditions for the synthesis of quinoxalines.
We have recently published a rapid method for the synthesis of benzimidazoles[40] using only methanol as solvent at room temperature with one-minute reaction time.
The unprecedented simplicity and efficiency of this system became the impetus for
our current study, in which we investigate the synthesis of quinoxalines via 1,2-dicarbonyl
compounds under similar experimental conditions. By mixing the reagents in 5 mL/mmol
methanol at room temperature for one minute in a vessel open to air, the reaction
between phenylenediamine 1a and glyoxal 2a gave impressive 99% GC conversion and 93% isolated yield of quinoxaline 3a (Table [1]).[41] The same reaction in ethanol also gave quantitative GC conversion, but somewhat
less 85% isolated yield of 3a. A survey of other solvents revealed that a broad spectrum of reaction media can
be employed, and 99% GC conversions were observed in acetonitrile, DMF, THF, ethyl
acetate, and chloroform. There seems to be a consistent relation between the GC conversions
and isolated yields.
Table 1 Solvent Screen for Quinoxaline Formation at One-Minute Reactiona
|
|
Entry
|
Solvent
|
Conversion (%)b
|
|
1
|
acetone
|
77
|
|
2
|
H2O
|
60
|
|
3
|
MeCN
|
99
|
|
4
|
EtOH
|
99 (85)c
|
|
5
|
MeOH
|
99 (93)c
|
|
6d
|
MeOHd
|
99 (88)c,d
|
|
7
|
DMF
|
99
|
|
8
|
THF
|
99
|
|
9
|
EtOAc
|
99
|
|
10
|
CHCl3
|
99
|
a Reaction procedure: to a stirred solution of diamine 1 (100 mg, 0.925 mmol) in a specified solvent (5 mL), glyoxal 2 (40%, 0.11 mL, 0.925 mmol) was added and stirred for 1 min at ambient temperature.
b GC conversion of starting material.
c Isolated yield.
d
1, 10 mL mmol–1 of solvent.
Only acetone and water gave lowered conversions in this assay (77% and 60%, respectively)
which appeared to be due to solubility problems in these solvents. The reaction is
relatively insensitive to the concentration, as a control experiment with doubled
amount of methanol (10 mL mmol–1) afforded the same full conversion and an only slightly diminished isolated yield
of 88% after one-minute reaction time. Thus, the amount of solvent employed can probably
be minimized but 5 mL mmol–1 was kept as standard for practical reasons. Based on this survey, the further studies
were conducted in methanol although it should be noted that a range of solvents are
viable.
We next studied various systems with different substituents on the diamine and the
dicarbonyl components in order to ascertain the generality of the simple reaction
conditions (Scheme [2]). Adding methyl groups, using either butane-2,3-dione or 4,5-dimethylphenylenediamine
or both as the electrophile, did not significantly alter the outcome of the corresponding
condensation products 3a–d which were formed in excellent 93–96% yields. Introducing halogens on the diamine,
such as 3k,l led to diminished but still good yields (62–66%). The 7-bromo-5-chloro-disubstituted
product 3e was also formed in similar yield (65%), whereas 6,7-dichloroquinoxaline (3g) was formed in 40% yield. Further tests with butane-2,3-dione and the dihalogenated
diamines also displayed diminished yields in this series (29–55% yields). Compound
3f was formed in the lowest yield (29%) and even increasing the reaction time up to
30 minutes did not alter this outcome. The main problem appears to be that conversion
of the starting material stops or becomes very slow (from GC analyses). The case of
3g was studied further to find a solution for improving the yields observed in the dihalogenated
systems. Upon heating the reaction mixture in a microwave at 100 °C for 5 minutes,
full conversion was observed, and 91% yield of 3g was isolated. Thus, heating is one effective solution, however, we were invested
in finding as simple conditions as possible for rapid conversion into product. Conducting
the reaction in acetic acid as solvent also gave full conversion of the starting material
and 85% yield of 3g was isolated after one-minute reaction. This also suggests, not surprisingly, that
the yield can be enhanced by acid catalysis, which was confirmed by an experiment
in methanol adding 10 mol% of acetic acid, which also gave full conversion and comparable
82% isolated yield of 3g. The formation of product 3f was vastly improved to 98% yield upon microwave irradiation at 100 °C for 10 minutes.
There seems to be several possible strategies for improving low-yielding cases while
maintaining very short reaction times.
Scheme 2 Scope of the reaction between diamine 1 and dicarbonyl compounds 2
Interestingly, with butane-2,3-dione and monohalogenated diamines, the products 3j and 3m were formed in very high 87% and 98% yields, respectively. Moreover, the 6-cyanosubstituted
system 3n was formed in 90% yield. A synergetic electronic combination may occur in these particular
systems ensuring rapid transformations. Further, diaryl diketones were briefly explored,
and 3o was formed in near quantitative yield. The dimethyl and monochloro systems 3p,q were also formed in excellent 91% and 89% yields, respectively, whereas the monobromo
system yielded only moderate amounts of 3r (51%). The chemistry is also compatible with substitution on the aryl diketone part,
as the ortho-chlorosubstituted variant yielded 3s in 80% isolated yield. There seems to be some tolerance towards sterically crowded
electrophiles. Next, heteroaryl diketones were employed with 2-furyl and 2-pyridyl
substituents. These worked excellently to generate fairly complex multiheteroaromatic
systems 3t–w in 75–96% yields. Finally, some unsymmetrical combinations were tested and 5-benzoylphenylenediamine
in combination with 1,2-propanedione yielded excellent 96% of products 3x/3x′ as an equimolar isomeric mixture. An equimolar isomeric mixture was also observed
with 1-phenyl-1,2-propanedione as electrophile, and 91% yield was isolated of 3y and 3y′. Lastly, 4,5-dimethylphenylenediamine was employed with indoyl-substituted oxocarboxylic
acid 2z to generate the 2-hydroxy-3-(3-indoyl)-substituted quinoxaline 3z in moderate 41% yield (NMR). The yield was substantially improved upon microwave
irradiation to 79%. In this case, one of the electrophilic sites is a carboxylic acid,
and the diminished electrophilicity is likely the reason for the attenuated reactivity.
In general, all products appeared to be stable upon isolation and storage, so this
cannot explain any diminished chemical yields. The compounds 3f, 3y, and 3z are novel molecules.[42] Overall, the rapid quinoxaline formation appears to have rather broad scope with
good to excellent yields obtainable in most cases and with temperature increase or
simple acid catalysis as strategies to boost yields in problematic cases.
Based on the results herein, and a comparison with many of the literature studies
employing various catalysts, heating, and prolonged reaction times, it is tempting
to conclude that many studies lack an important control experiment without added catalyst.
Moreover, prolonged reaction times and the need for heating of simple substrates may
even suggest that the ‘catalysts’ employed in some cases actually decrease the reaction rates. This could occur if a metal predominantly coordinates with one
or both of the substrates and thus, would reduce the effective concentration of reacting
species and require more time or energy to effect an acceptable reaction outcome.
Based on these considerations and the results in this paper, we would like to strongly
advocate that synthetic studies of quinoxaline formation using the classical condensation
reaction should commence with the simple conditions described herein and that any
novel catalytic reactions should be compared directly to the ‘uncatalyzed’ counterpart
to assess the true catalyst performance. Lastly, it should be widely known and intuitive
for practicing synthetic chemists that this classical condensation reaction can occur
in minutes and without addition of catalysts. This does not appear to be the case
upon examination of the literature.
In order to demonstrate further the applicability of these reaction conditions, five
examples were conducted in experiments on larger scales (Scheme [3]).[41] Compounds 3α, 3o, and 3w were generated in high to excellent yields (91%, 70%, and 94% respectively) at 1
g scale using the basic conditions and methanol as solvent. If the reaction solvent
was ethyl acetate, this would streamline the workup considerably since removal of
the reaction solvent becomes unnecessary. Thus, we conducted the reaction at 10 g
scale in ethyl acetate and quinoxalines 3a and 3α were readily isolated in impressive 93% and 85% yields, respectively. This study
strongly suggests that this should be a method of choice for the construction of such
structures on scale.
Scheme 3 Scale-up of the quinoxaline synthesis
In summary, we have revisited a classical transformation and report on improved synthesis
efficiency and broadened scope of quinoxaline formation via the rapid condensation
between aryldiamines and 1,2-dicarbonyl compounds. The cyclocondensation occurs fast
under remarkably simple reaction conditions in medium to excellent chemical yields.
Using methanol as solvent, the reaction typically proceeds at room temperature, open
to air, and with only 1 minute reaction time. Problematic cases can be solved with
simple acid catalysis or heating while maintaining very short reaction times. The
practical nature and scalability of this green approach makes it an obvious starting
point and method-of-choice for the synthesis of a range of quinoxalines.
